With several new therapies becoming available, treatment of metastatic breast cancer (mBC) is evolving. The objective of this study is to describe patient characteristics, treatment patterns and real-world clinical outcomes in post-menopausal women with ER+, HER2- mBC and to obtain insight into patient outcomes and potential unmet needs with current therapies.
Trang 1R E S E A R C H A R T I C L E Open Access
Treatment patterns and real world clinical
outcomes in ER+/HER2- post-menopausal
metastatic breast cancer patients in the
United States
Giovanni Zanotti2, Matthias Hunger1*, Julia J Perkins2, Ruslan Horblyuk2and Monique Martin3
Abstract
Background: With several new therapies becoming available, treatment of metastatic breast cancer (mBC) is evolving The objective of this study is to describe patient characteristics, treatment patterns and real-world clinical outcomes in post-menopausal women with ER+, HER2- mBC and to obtain insight into patient outcomes and potential unmet needs with current therapies
Methods: The current study is a physician survey followed by a retrospective chart review of patient medical records by physicians in the US between March and April 2015 One hundred three physicians were asked to complete an online survey aiming to understand their satisfaction and expectations with current available treatments and potential areas of unmet need for mBC patients Medical records from 178 females were
extracted for the chart review Using these data from medical records, patient characteristics and treatment patterns were analyzed descriptively Time to progression (TTP) on first line, and progression-free survival (PFS)
on second and third line of therapy were analyzed using the Kaplan-Meier method
Results: Sixty-seven percent (n = 119) of patients had metastatic disease at initial diagnosis of breast cancer Mean age at chart data extraction was 65.8 (SD: 9.4) years Aromatase inhibitors (AIs) were prescribed for 58% and around 13% of patients in first line and second line, respectively Chemotherapy was prescribed to 14% in first line and 31% in second line Median TTP on first line therapy was 12 months for patients receiving AIs as compared to 7.9 months for patients receiving chemotherapy Across all treatment lines, bone pain and fatigue were reported as the main symptoms associated with disease progression which had an impact on patient quality of life Physicians expressed that prolonging life was deemed the most important treatment goal, followed by preservation or improvement of quality of life
Conclusion: In this study the majority of patients received endocrine therapy as first line treatment and current therapies still resulted in a short time to progression in first line Results from the chart review and the
physician survey highlight a quantitative unmet need for more effective treatments which delay disease
progression and improve survival outcomes while maintaining quality of life
Keywords: Post-menopausal metastatic breast cancer, Treatment patterns, Physician survey, ER+/HER2
* Correspondence: mhunger@mapigroup.com
1 Mapi, Konrad-Zuse-Platz 11, 81829 Munich, Germany
Full list of author information is available at the end of the article
© The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver
Trang 2Breast cancer (BC) is the most common cause of cancer
death in women worldwide and estimated to be
respon-sible for almost 460,000 deaths in 2008 [1] Estimates
from the United States for 2015 show that breast cancer
accounts for 29% of all new cancers diagnosed and 15%
of all cancer deaths in women [2, 3] When diagnosed in
early stages, treatment of BC is generally more effective
resulting in a 5-year overall survival rate of 99% for stage
I (localised stage) and 85% on average in regional stage,
compared with only 25% for the metastatic stage IV [2]
However, early stage BC can recur and it is estimated
that 20 to 30% of all patients diagnosed with early stage
BC will eventually progress to metastatic disease over a
lifetime [4] Metastatic breast cancer is when breast
can-cer has spread beyond the breast and local lymph nodes
under the arm to other areas of the body The most
common sites of metastases are the bones, lungs, liver
and brain
Approximately 6–10% of new breast cancer cases are
diagnosed initially at stage IV or mBC [5] and it has
been estimated that 155,000 Americans are currently
living with mBC [6] According to the 2008 American
Society of Clinical oncology (ASCO) symposium report,
the median survival rate after diagnosis of mBC was
three years and no statistically significant improvement
has been established since then [7, 8]
The majority of diagnosed breast cancers is Estrogen
receptor-positive (ER+) and Human Epidermal Growth
Factor Receptor 2 negative (HER2-) Endocrine therapy
is the major treatment for ER+ and HER2- metastatic
breast cancer [9] In the last two decades, the third
gen-eration of aromatase inhibitors anastrozole, letrozole
and exemestane have become the standard hormonal
treatment for post-menopausal women in both advanced
and early disease [9] The efficacy of these compounds
in terms of response rates in first line metastatic patients
are up to 40% with all initial responders eventually
de-veloping resistance over time, meaning that there is an
ongoing need in this population [10]
According to the National Comprehensive Cancer
Network (NCCN) guideline, it is recommended to
con-tinue endocrine therapy after progression with a first
endocrine agent, unless there is significant visceral
bur-den or rapid progression of disease, where in this case
chemotherapy is recommended [11] Other endocrine
therapies options include selective oestrogen receptor
modulators like tamoxifen or selective oestrogen
recep-tor degraders like fulvestrant
However, real world treatment patterns and outcomes
among patients with ER+, HER2- mBC are still not well
characterized A literature review by Boswell et al [12]
examined disease burden and treatment outcomes in
second-line therapy of patients with ER+ advanced
breast cancer The authors concluded that there is insuf-ficient evidence on effectiveness outcomes to quantify the unmet need in ER+ patients, and this gap warrants further research Swallow et al [13] conducted an ana-lysis of MarketScan databases of patients with HR+, HER2- mBC between 2002 and 2012 They found that most patients initiating treatment with endocrine ther-apy (ET) received only one line of ET before discon-tinuation or transition to chemotherapy Gaps in knowledge remain despite the availability of recent chart review studies in HR+, HER2- mBC [14–16] A better understanding of patient characteristics, real world variations in treatment and their impact on clin-ical outcomes is needed to identify limitations of cur-rently available therapies and patient needs
The objective of this study is to describe patient char-acteristics, clinical outcomes observed in real-world as well as identification of aromatase inhibitors early non responder’s characteristics in post-menopausal women with ER+, HER2- mBC and to obtain insight on poten-tial unmet needs in these patients
Methods
Data source
Our study had two distinct components: a cross-sectional physician survey and a retrospective medical record review conducted by participating physicians be-tween March and April 2015 Physicians specializing in medical oncology or hematology/oncology and treating patients with post-menopausal ER+, HER2- metastatic breast cancer were invited to participate from a US online physician panel Physicians were eligible for the survey and the chart review if they personally treated 12
or more ER+, HER2- metastatic breast cancer patients within the last six months Also, physicians were re-quired to provide informed consent and to have been practicing medicine for the treatment of ER+, HER2-mBC patients for between two and thirty years To achieve a sample representative of physicians treating mBC in the US, soft quota restrictions were applied for the region where physicians practice and approximately 60% of sites were required to be community-based practices
All potential physician participants were screened for study eligibility using a standardized screening ques-tionnaire developed for the study No more than two physicians were allowed to be grouped per practice Eli-gible physicians were asked to participate in an online survey including 25 questions on physicians’ perception
of quality of life among patients ER+, HER2- mBC, physicians’ satisfaction with currently available treat-ments and potential areas of unmet need, and physician and patient interactions and dialogue The survey was pilot-tested on three physicians and minor changes
Trang 3were made to the survey to reflect their comments.
After completing the online survey, physicians were
asked to extract individual patient data from medical
records of two randomly selected patients and fill out
an online case report form Only de-identified data
from the charts were abstracted and Institutional
Review Board (IRB) approval was obtained for both the
physician survey and the patient medical record data
201500093) Research was performed in accordance
with the Declaration of Helsinki
Patient selection
Records of female patients were eligible for chart data
abstraction if they had a confirmed post-menopausal
sta-tus per local practice guidelines at time of mBC
diagno-sis, had a confirmed diagnosis of metastatic breast
cancer based on histological or cytological findings and
had confirmed ER+ and HER2- BC per local practice
guidelines Furthermore, patients had to have received
care from the same physician from diagnosis of mBC to
the last available encounter in the medical record and
had to have completed at least 2 lines of breast cancer
therapy in the mBC setting between January 1, 2008,
and March 1, 2014 This means that patients that died
during first-line therapy or before initiation of
second-line therapy could not be enrolled in the study
Com-pletion included comCom-pletion of prescribed treatment,
disease progression, or discontinuation of treatment
due to adverse events, loss to follow-up, patient
request, or death Patients were not eligible for the
chart review if they had evidence of other concurrent
malignancy, except adequately treated non-melanoma
skin cancer or other noninvasive (in situ) neoplasms at
the time of diagnosis of ER+, HER2- metastatic breast
cancer Patients who participated in a clinical trial or
other interventional study related to breast cancer for
any treatment in the metastatic setting were not eligible
for the study either Participants of observational
stud-ies or adjuvant clinical trials were allowed A quota for
survival status was applied to the selection of patients
to ensure that 80% of patients selected were still alive
at the date of data abstraction
Study outcomes
Chart data abstracted by the treating physician included
information on demographic characteristics, disease
his-tory, treatments received by line of therapy, start and
stop dates of the therapies, and reasons for treatment
discontinuations Primary reasons for discontinuation
in-cluded – amongst others – completion of treatment as
planned, disease progression, drug resistance, toxicities/
side effects, or death Time to disease progression on
first-line therapy was defined as the time from the start
of the therapy to the date of documented disease pro-gression Patients who completed first-line treatment as planned or who discontinued treatment for reasons other than disease progression were censored at the day
of treatment completion or treatment discontinuation, respectively As inclusion criteria required having com-pleted at least two treatment lines, no deaths were observed during first line therapy However, as some pa-tients died while on second or third line therapy, progression-free survival (PFS) rather than TTP was analyzed for second and third line treatments PFS on second and third line therapy was defined as the time from start of treatment to the date of documented disease progression or death Patients who completed second or third line treatment as planned or who dis-continued treatment for reasons other than disease progression were censored at the day of treatment completion or treatment discontinuation Overall sur-vival (OS) was defined as time from start of first-line treatment to death from any cause For PFS and OS, patients without an event were censored at their chart abstraction date
Statistical analysis
All statistical analyses were descriptive in nature Sum-mary statistics were calculated to describe physicians’ re-sponses in the survey and to describe demographics, clinical characteristics, and treatment patterns of pa-tients from the chart review study For continuous data, the mean, standard deviation and median are presented For categorical data (including yes/no categories), the frequency and percentage in each category are pre-sented Analyses were stratified by line of treatment and type of treatment received where applicable Time-to-event endpoints such as TTP on first-line therapy, PFS
on second or third line therapy or OS were analyzed using Kaplan-Meier methods to appropriately take into account censored observations
To explore the potential unmet need of patients receiving aromatase inhibitors who had an early treatment discon-tinuation, further bivariate analyses in this subgroup were conducted For these analyses, early treatment discontinu-ation was defined using a cut-off of five months Reasons for treatment discontinuation included progression, death, drug resistance or toxicities/side effects
Results
A total of 510 physicians were contacted through the online panel Of those, 130 physicians were screened out because they did not meet inclusion criteria, and 277 physicians did not successfully complete the survey A total of 103 physicians completed the survey and ab-stracted chart data from 178 post-menopausal patient medical records with confirmed ER+/HER2- mBC
Trang 4Chart review
Patient characteristics
Of the 178 patients with confirmed metastatic disease
and for whom data was extracted 119 (66.9%) had
meta-static disease at initial diagnosis of ER+ HER2- breast
cancer (Table 1) Eleven percent were initially diagnosed
at stage IIIA, IIIB or IIIC, while 40 (22.5%) patients had
a history of early disease The mean age at chart data
ex-traction was 65.8 years Distant metastases were most
common in the bone (73.0%;n = 130) followed by lung/
pleura (36.5%;n = 65), lymph nodes (32.0%; n = 57) and
the liver (21.4%;n = 38) The mean age at progression to
metastatic disease was 62.9 years Most patients (89.3%,
n = 159) had an Eastern Cooperative Oncology Group
(ECOG) status of 0 or 1 at the time of diagnosis of
mBC For the 65 patients (36.5%) with a history of
adju-vant treatment, median duration of adjuadju-vant treatment
was 36 months Main reasons for stopping earlier,
non-metastatic therapy were successful completion of
planned treatment course (43.1%) and progression to
metastatic disease (41.5%)
Treatment patterns
Aromatase inhibitors (anastrozole, letrozole and
exemes-tane) were prescribed for the majority of patients in first
line (103 out of 178; 58%) and for only 13% of patients
in second line (23 out of 178) Other therapies (e.g
tamoxifen, fulvestrant or everolimus), or aromatase in-hibitors combined with chemotherapy was given to 28% (50 out of 178) of patients in first line and 55.6% (99 out
of 178) of patients in second line Among the 50 patients receiving other therapies in first line, 43 patients were treated by endocrine therapy and the seven remaining patients were treated by everolimus (n = 4), bevacizu-mab (n = 2) and lapatinib (n = 1) Chemotherapy only was administered in 14.0% (25 out of 178) of patients in first line and in 31.5% (56 out of 178) of patients in sec-ond line (Fig 1) Patients receiving chemotherapy in first line were more likely to have visceral disease than pa-tients receiving other therapies (79.2% vs 49.7%,
p = 0.0071)
As shown in Fig 2, the most frequently described treatment in first line was the aromatase inhibitor ana-strozole (63 out of 178; 35.4% patients) Thirty-eight per-cent (n = 24) of patients receiving anastrozole in first line switched to fulvestrant in second line Letrozole was administered in first line for 19.1% (34 out of 178) of patients For these patients, the everolimus plus exe-mestane treatment combination and the fulvestrant endocrine therapy were the most frequently given subse-quent treatment in second-line (for both everolimus + exemestane and fulvestrant: 32.4%; 11 out of 34) Exemes-tane was prescribed for only 3.4% of patients in first line (6 out of 178)
Table 1 Patients characteristics– from chart review
BC breast cancer; ECOG: Easter Cooperative Oncology Group; mBC: metastatic breast cancer
a
Definition of ECOG performance statuses; 0: Fully active, able to carry on all pre-disease performance without restriction; 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g light house work, office work; 2: Ambulatory and capable of all self-care but unable to carry out any work activities Up and about more than 50% of waking hours; 3: Capable of only limited self-care, confined to bed or chair more than
Trang 550
25
0 20 40 60 80 100 120
Aromatase Inhibitors
Other Chemotherapy
Treatment pattern in first-line
23
99
56
0 20 40 60 80 100 120
Aromatase Inhibitors
Other Chemotherapy
Treatment pattern in second-line
Fig 1 Treatment patterns in first (panel a) and second line (panel b) - n = 178; from chart review Aromatase inhibitors: anastrozole, letrozole, exemestane and anastrozole + exemestane Chemotherapy: capecitabine, docetaxel, paclitaxel, paclitaxel + carboplatin, docetaxel +
cyclophosphamide, 5 fluorouracil, carboplatin, carboplatin + gemcitabine, cyclophosphamide + doxorubicin, docetaxel + carboplatin, goserelin, nab- paclitaxel Other: tamoxifen, fulvestrant, everolimus + exemestane, anastrozole + paclitaxel, anastrozole + fulvestrant, anastrozole + tamoxifen, anastrozole + docetaxel, bevacizumab, letrozole + fulvestrant, anastrozole + anthracycline + cyclophosphamide, anastrozole + paclitaxel + anthracycline, bevacizumab + anastrozole + tamoxifen, everolimus, everolimus + letrozole, everolimus + tamoxifen, exemestane + carboplatin, letrozole + zoledronic acid, letrozole + paclitaxel, tamoxifen + goserelin, vinorelbine + lapatinib, lapatinib, toremifene-citrate Note:
“Other” refers to other treatments than aromatase inhibitors and chemotherapy agents
63
34
6
24 11
9 3 3 3 2 2 1 1 1 1 1 1 11 11 3 2 1 1 1 1 1 1 1 4 2
Anastrozole Fulvestrant Everolimus + Exemestane
Exemestane Docetaxel Letrozole Capecitabine Everolimus Tamoxifen Paclitaxel Anastrozole + Fulvestrant Anastrozole + Bevacizumab Everolimus + Exemestane + Fulvestrant
Exemestane + Placlitaxel Toremifene - citrate Letrozole Everolimus + Exemestane
Fulvestrant Capecitabine Everolimus Everolimus + Anastrozole Exemestane + Doxorubicin Fulvestrant + Docetaxel + Doxorubicin
Tamoxifen Nab-paclitaxel Docetaxel Paclitaxel Exemestane Fulvestrant Placlitaxel
First line Second line Fig 2 Treatment patterns after aromatase inhibitors in first line ( n = 103) – from chart review Data show absolute frequencies of treatments received in second line for patients that received anastrozole ( n = 63), letrozole (n = 34) or exemestane (n = 6) in first line
Trang 6Disease progression
In first line, patients treated with chemotherapy
pro-gressed earlier (median time to disease progression:
7.9 months; 95% CI: 6.0 to 8.3) than those treated with
aromatase inhibitors (12.0; 95% CI: 10.0 to 13.1) or other
treatments including combination therapies of
aroma-tase inhibitors and chemotherapy (11.9; 95% CI: 7.0 to
17.3), although the difference was not statistically
signifi-cant – see Table 2 The Kaplan Meier curve for time to
disease progression (TTP) in the subset of patients
re-ceiving aromatase inhibitors in first line (n = 103) shows
that the probability of being progression-free at 3 and
5 months after start of first line therapy was 81.6% and
74.7% respectively (Fig 3) In second line, median PFS
was 7.3 (95% CI: 5.1 to 11.2), 7.4 (95% CI: 5.7 to 8.4)
and 8.1 (95% CI: 7.0 to 12.0) months for patients
re-ceiving chemotherapy, aromatase inhibitors and other
treatments, respectively On third line treatment, the
median PFS was higher for patients treated by
chemo-therapy compared with those treated by aromatases
inhibitors and other treatments: 9.0 months for
chemo-therapy, 8.0 months (95% CI: 3.4 to 12.0) for aromatase
inhibitors and 5.2 months (95% CI: 4.0 to 14.1) for
other treatments
As per inclusion criteria, 80% of patients were required
to be alive at data abstraction Accordingly, the Kaplan
Meier estimate for the probability of survival at
24 months after start of first line treatment was 87.6%
Reasons for treatment discontinuations
The most frequently reported primary reason of
treat-ment discontinuation was efficacy in terms of disease
progression and this was true for agents received in all
the three first treatment lines Disease progression
accounted for 76.4% (168 out of 220 agents) of reasons
reported in first line, 71.6% (169 out of 236 agents) of
reasons in second line, and 50.4% (57 out of 113 agents)
of reasons in third line (Table 3)
Across all treatment lines, bone pain and fatigue were reported as the most frequent symptoms associated with disease progression Bone pain was reported for 54.4% (n = 81) of the 149 patients that progressed in first line and for 56.9% (n = 74) of the 130 patients that pro-gressed in second line Fatigue was reported for 41.6% (n = 62) of patients in first line and 43.8% (n = 57) of pa-tients in second line
Characteristics of patients early discontinuing aromatase inhibitors
Characteristics of patients who discontinued treatment with aromatase inhibitors earlier than 5 months after treatment initiation (n = 26) were not significantly differ-ent from the 76 patidiffer-ents who discontinued treatmdiffer-ent later than 5 months (Table 4) However, early treatment discontinuation was less likely in patients receiving letrozole than in patients receiving anastrozole or exe-mestane (p = 0.0036)
Physician survey Physician characteristics
Physicians had treated on average 30 pre- and 50 post-menopausal mBC ER+ HER2- patients in the past
6 months, respectively Seventy-two of the 103 physi-cians were working in a clinic-based practice or had an office, whereas 13 physicians provided care in a commu-nity hospital based practice (25, 23, 25 and 30 physicians
of the 103 physicians were based in North East, Middle-West, West and South, respectively) The remaining 18 physicians were from university hospitals, tumour cen-ters or an NCI-designated cancer center
According to the physicians surveyed, on average 32%
of all their newly diagnosed post-menopausal BC pa-tients had metastatic disease at initial diagnosis of BC
Table 2 Time to disease progression and PFS by drug category and treatment line– from chart review
obs a Median
(months)
95% confidence interval p-value b
Lower limit Upper limit Time to disease progression on first-line therapy
(months) from start of first-line therapy
Progression- free survival on second line therapy
(months) from start of second-line therapy
Progression- free survival on third-line therapy
(months) from start of third-line therapy
PFS Progression-free survival; NE Not Estimable
a
Censored patients are patients who have not had an event of disease progression, either because they dropped out from the trial for reasons other than disease
b
Trang 7Thirty-three percent of patients were diagnosed at an
early stage of BC (stage I or II) while the mean
percent-age of patients diagnosed at stpercent-age IIIA, IIIB or IIIC was
13%, 11% and 12% respectively
Treatment goals and treatment selection
Physicians were asked about the three most important
treatment goals for first-line therapy As is shown in
Table 5, prolonging life was deemed the most important
reason for treatment (58.3%) The most frequently
men-tioned responses for the second most important reasons
of treatment were quality of life
improvement/preserva-tion (23.3% for quality of life improvement and 19.4%
for quality of life preservation), respectively For the
third most important reason, it was symptom relief
(24.3%)
Physicians used hormonal therapies (aromatase inhibi-tors or tamoxifen) for around half of patients (51.9%) in first-line, followed by chemotherapy which was given to 17.6% of patients In second-line, a fifth of patients re-ceived either oral hormonal therapy (21.1%), exemestane plus everolimus (22.4%) or other hormonal therapy (21.7%), respectively, and 25.6% of them were treated with chemotherapy In third line, treatment patterns be-come even more diverse but with more patients receiv-ing chemotherapy (35.8%): around 21.3% of patients received exemestane with everolimus and 12.6% and 16.3% of patients received oral hormonal and other hor-monal therapy, respectively (Table 6)
Expectations on and limitations of treatment success
Physicians were asked to provide their experience with duration of PFS and OS for current treatments In their
Table 3 Primary reasons for treatment discontinuation– from chart review
Primary reason for treatment
discontinuation
First line ( N = 220 a ) Second line ( N = 236 a ) Third line ( N = 113 a )
There were more agents than patients per line (e.g 220 agents vs 178 patients in first line) as physicians were asked to provide reasons of discontinuation for every single agent rather than for every therapy
mBC metastatic breast cancer
a
Fig 3 Time to progression on first line therapy with aromatase inhibitors – from chart review Survivor function at 2 months: 0.845 / Survivor function at 3 months: 0.816 / Survivor function at 5 months: 0.747; median time to progression: 12.0 months
Trang 8experience, duration of PFS for the first treatment in
ER+ HER2- mBC patients is around 13 months
Physi-cians also reported that they consider on average an
increase of 7.4 months (median 6 months) as the
mini-mum clinically meaningful improvement in
progression-free survival over current standard of care for a new
treat-ment of post-menopausal ER+, HER2- mBC In terms of
overall survival from start of first treatment, physicians’
current experience was close to 29 months or 2.4 years
The physicians were asked to list the main treatment limitations of current treatments on a scale from 1 to 5 (5: very substantial, 4: substantial, 3: moderately, 2: somewhat, 1: not at all substantial) The main limitations reported were efficacy and safety/tolerability of treat-ments (Table 7) Focusing on aromatase inhibitors only, efficacy was still the limitation that most physicians per-ceived as either substantial or very substantial (46.6%), but an equal proportion also considered drug resistance
as a substantial or very substantial treatment limitation (Table 8)
Discussion The present study investigated patient characteristics, treatment patterns and time to disease progression through a retrospective review of medical records from ER+/HER2- mBC patients in the US and also assessed characteristics of patients experiencing early treatment discontinuation Furthermore, the empirical real-world data from the chart review were supplemented, for some aspects, by a physician survey conducted among the 103 physicians who extracted the data
Table 5 Goal of treatment– from physician survey (n = 103)
First Rank Second Rank Third Rank
Prolongate life 60 58.3% 13 12.6% 14 13.6%
Stabilize disease 1 1.0% 12 11.7% 11 10.7%
Preserve Quality of life 11 10.7% 20 19.4% 12 11.7%
Delay chemotherapy 5 4.9% 6 5.8% 18 17.5%
Improve quality of life 12 11.7% 24 23.3% 16 15.5%
Table 4 Treatment discontinuation on first-line therapy with aromatase inhibitors before vs after 5 months - from chart review
≤ 5 months (N = 26) Treatment discontinuation> 5 months ( N = 76) p-value
ECOG performance status at the time
of diagnosis of mBCa
mBC metastatic breast cancer
One patient using aromatase inhibitors in first-line was excluded due to treatment discontinuation (patient choice) at 3 months
a
Definition of ECOG performance statuses; 0: Fully active, able to carry on all pre-disease performance without restriction; 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g light house work, office work; 2: Ambulatory and capable of all self-care but unable to carry out any work activities Up and about more than 50% of waking hours; 3: Capable of only limited self-care, confined to bed or chair more than 50% of walking hours
b
Exact Fisher test
Trang 9The chart review data showed that following mBC
diagnosis, the majority of patients received endocrine
therapy (82%, including 58%(103/178) of aromatase
in-hibitors and 24% (43/178) of other ET) as a first-line
treatment, with the aromatase inhibitors anastrozole and
letrozole being the most frequently prescribed therapies
However a significant proportion (14%) of patients
re-ceived chemotherapy (including chemo monotherapy or
chemo combination therapies) as the first-line treatment
The potential reasons for chemotherapy use in first line
could be concerns about endocrine resistance or the
higher frequency of visceral metastases among these
pa-tients [17]
These findings are consistent with previous studies
examining treatment patterns in ER+/HER2- mBC
pa-tients: Macalalad et al (2015) [15] who described
treatment patterns in post-menopausal women with
HR+/HER2- metastatic breast cancer in a US
retro-spective chart review, presented first line treatment
patterns with 84% of patients treated with endocrine
therapy (or treatment in combination with ET), 14% of
them with chemotherapy (monotherapy or
combin-ation of chemotherapy agents) and 2% with other
ther-apies (n = 144) Xie et al performed a chart review in
the US for the same population of patients, they
showed that 87% and 13% of them were under
endo-crine therapy and chemotherapy respectively at
base-line in patients with a single metastasis [16]
The median time to progression for patients included
in this chart review who were treated with aromatase in-hibitors in first line was 12 months This is consistent with estimates from previous studies which reported a time to progression between 8.2 months and 13.1 months for anastrozole used in first line [18–20] With a median
of 8 months, time to progression during first-line ther-apy for patients receiving chemotherther-apy was markedly shorter Median PFS on second line therapy was shorter than on first line and did not significantly differ by type
of therapy received in first line Regarding patients treated by aromatase inhibitors in first line, the median time to progression in third line was similar for those treated either by chemotherapy or aromatase inhibitors (9 months and 8 months respectively) This last clinical outcome is consistent with the NCCN guideline who recommends chemotherapy after three sequential endo-crine therapy regimens However chemotherapy is asso-ciated with important side effects which impair patient quality of life
The overall findings of the study highlight a quantita-tive unmet need for more effecquantita-tive treatments which delay disease progression and improve survival outcomes while maintaining quality of life This was also expressed
by the physicians, who participated in the survey, stating that prolongation of life, delaying deterioration in symp-toms, and preserving or improving quality of life repre-sent the most important treatment goals for them Also,
Table 6 Treatment selection: Proportion of therapies for post-menopausal ER+, HER2- metastatic BC patients used in first-line, second-line and third-line in the past 6 months– from physician survey (n = 103)
Oral hormonal therapy (e.g., tamoxifen, aromatase inhibitors) 51.91% 32.48 21.14% 22.40 12.55% 15.02
-BC Breast cancer; SD standard deviation
Table 7 Limitations of treatment success in first-line ER+, HER2- mBC patients - overall by analysis of categories– from physician survey (n = 103)
Not at all substantial Not at all substantial Moderately substantial Substantial Very substantial
mBC metastatic breast cancer
Trang 10the majority of physicians considered limited efficacy as
the most substantial limitation of currently available
treatments Finally, the survey also indicated that
physi-cians consider an increase in progression-free survival of
7 months or more as clinically relevant to patients
The chart review observed that 74.5% of patients
treated with aromatase inhibitors in first line have not
experienced disease progression after 5 months, while
25.5% of patients did It was hypothesised that this
group of early progressors represents a subgroup of
pa-tients who are early non-responders to aromatase
in-hibitors and who ideally should be prescribed another
treatment after progression or ideally should be
identi-fied early so that early progression can be prevented by
using a different treatment The current study was not
able to identify specific clinical or patients
characteris-tics that could be predictive of early non-responders,
mainly due to the low numbers of patients available for
this analysis However, there were fewer patients treated
with letrozole in first line who discontinued before
5 months as compared to those continuing beyond
5 months (5 (19.2%) vs 29 (38.2%), p = 0.0036) This
might be related to potentially better efficacy of
letro-zole in comparison with other aromatase inhibitors In
previous in vivo measurement studies, letrozole
dem-onstrated a better biochemical efficacy with a greater
suppression of plasma oestrogen levels than anastrozole
at clinical doses [21, 22] However, a 5-year
compara-tive efficacy study of letrozole and anastrozole in
post-menopausal hormone receptor-positive early BC didn’t
demonstrate any significant difference in disease free
progression and survival rates [23]
Despite clear guidelines on the preferential use of
mul-tiple lines of endocrine therapy versus chemotherapy in
advanced ER+ BC, a review of practice patterns using
data from 2004 to 2010 have shown that these therapies
were not being used as recommended [15] The current
study provides a more recent review of practice patterns
in a rapidly evolving treatment landscape using data
from 2008 to 2014 The study further adds to current
knowledge on real-world outcomes in mBC since
previ-ous studies did not report data on clinical outcomes
such as time to progression [13, 15] Also, similar chart review studies in mBC patients did not describe treat-ment patterns [14, 16] or evaluated the effectiveness of specific treatment options only [14, 24] Finally, by pro-viding both, quantitative data from a chart review and qualitative data from the accompanying physician sur-vey, the study provides a comprehensive picture of treat-ment selection, clinical outcomes, treattreat-ment goals and current limitations of treatments as perceived by physi-cians and their patients
Though many efforts were undertaken to overcome these, this study has limitations inherent to the retro-spective nature of the chart review study, the descriptive nature of the statistical analyses and the subjective na-ture of the physician survey It is further possible, that the results were confounded by potential factors that were not identified A key limitation for analyses related
to the early non-responders was the small sample size (n = 26) which may have led to us not being able to identify specific patient characteristics for this patient subgroup Also, it must be kept in mind that inclusion criteria required patients to have completed at least two lines of therapy and that a quota for survival status was used to ensure that 80% of patients were still alive at the date of data abstraction While this ensured that there are sufficient data on treatment patterns in first- and second line, it may bias results towards “healthier” or longer living patients in this population For this reason, the analysis of OS must be considered with caution Despite these limitations the sample of physicians was representative of physicians treating mBC in the US and the current study provides important insights about real world outcomes for ER+ HER2 mBC patients and their current unmet medical need
Conclusion This study provides new evidence on treatment patterns and real-world clinical outcomes for post-menopausal ER+ HER2- metastatic breast cancer patients in the US The retrospective chart review revealed that a majority of 82%
of patients received endocrine therapy as first-line treat-ment and showed that current therapies in ER+
HER2-Table 8 Limitations of treatment success in first-line ER+, HER2- mBC patients - aromatase inhibitors only– from physician survey (n = 103)
Not at all substantial Not at all substantial Moderately substantial Substantial Very substantial
mBC metastatic breast cancer